Smith-Lemli-Opitz Syndrome (SLOS) is a rare genetic condition
of impaired cholesterol biosynthesis, with most of affected individuals
simultaneoulsy exhibiting at least some of the symptoms of autism.
The figures on the rates of formal autism diagnosis in individuals
with SLOS vary but appear to be somewhere between 50-75 percent,
among the highest of single gene disorders associated with autism
[16761297].
While supplementing dietary cholesterol frequently eliminates
or ameliorates many of the feeding and growth problems of SLOS,
it has been observed recently the autistic behaviors of children
with SLOS can also be reduced or even eliminated by treatment
with supplementary dietary cholesterol. In addition to behavioural
and language-delay problems, individuals with SLOS often suffer
from several gastrointestinal problems, including severe reflux
and constipation, immune deficiency and sleep problems.

Disturbances in membrane sterol content in SLOS is thought to
directly contribute to various cellular abnormalities in observed
in this disease, which include significantly increased calcium
permeability as well as reduced folate uptake (see Oxidative
Stress). Most interestingly, partial restoration of the excessive
calcium influx pathway was observed following cholesterol enrichment
[16258167].
Increasing evidence indicates that membrane cholesterol is capable
of modulating function of voltage gated calcium channels. Caveolae,
including caveolae-like plasma domains in neurons, and transverse
(T-) tubules are membrane lipid-raft structures rich in caveolin,
cholesterol and glycosphingolipids, as well as VGCC. Recent results
have shown that a depletion of membrane cholesterol alters caveolae
and T-tubules. Cholesterol and LTCC occupy a similar molecular
location in the membrane. In one study application of a a cholesterol-sequestering
drug resulted in significant reduction in caveolae and T-tubule
areas and to a significant reduction of LTCC current, suggesting
that membrane cholesterol content modulates their function, and
that both lowered and excessive cholesterol levels can modulate
calcium currents [14724204,
2054935].
This is proposed to be one possible mechanism behind the observed
reduction in autistic symptoms in SLOS following supplementation
of dietary cholesterol. Another possible mechanism to be taken
into consideration is the effect of cholesterol on several serotonin
receptors and G-protein and ligand bindings of those receptors
(see Neurotransmitters).

In another study the addition of Caveolin-1 to cultured neurons
resulted in increased levels of membrane cholesterol and reduction
in calcium currents, thus showing that caveolin-1 also influences
neuronal VGCC activity [16040758].

Following the above findings, it is proposed that the opposite
effect might exist, whereas dysregulation of VGCC could under
certain conditions directly influence the membrane structure,
including the synthesis and/or levels of cholesterol and caveolin
[11353331].
In support of this hypothesis is the finding from human fertility
studies demonstrating that cholesterol synthesis can be significantly
increased in sperm treated with nifedipine, a calcium channel
antagonist [link].

Abnormalities of cholesterol metabolism have been observed in
more common forms of autism, with substantial numbers of individuals
showing lowered levels as compared to controls [16874769],
while elevated levels of cholestorol have been observed in individuals
with Asperger's syndrome [17123635].
In addition to cholestorol levels, results of a study investigating
brain high energy phosphate and membrane phospholipid metabolism
provided further evidence of undersynthesis and increased degradation
of brain membranes in autism. It was observed that membrane building
blocks decreased, and levels of membrane breakdown products increased
parallel to a decline test performance abilities in subjects with
autism [8373914].

In addition to the above, it is worth mentioning that one of the
downstream reactions in neurons following elevation in the levels
of intercellular calcium is the activation of several lipases,
proteases, and endonucleases that attack the structural integrity
of the cell. Calcium also activates phospholipase C, which promotes
a progressive breakdown in the phospholipid components of the
both plasma and intercellular membranes.